DESCRIPTION (Adapted from the application): The overall purpose of this study is to assess in vivo cognitive and neural impairments in patients with Frontotemporal Degeneration (FTD). This will also serve as the clinical core for the program project. In specific aim l, the applicants will administer a battery of cognitive and behavioral measures to distinguish FTD from Alzheimer?s disease (AD). They will test the specific hypothesis that core characteristics of FTD seen in patient subgroups include: l) an inattentive state with poor initiative, 2) a dysexecutive syndrome with poor strategic processing, 3) a progressive non-fluent aphasia (PNFA) with non-fluent speech, and 4) a disinhibited bizarre affect. They will follow these patients longitudinally with this battery and a "Brief Frontotemporal Exam" abstracted from the full battery. They will also test the hypothesis that dissociable executive components contribute to the cognitive and behavioral limitations of FTD subgroups such as poor attention, impaired strategic processing, limited short-term memory, and poor control over inhibition. In specific aim 2, they will use a quantitative, whole-brain, perfusion fMRI technique to demonstrate the differing anatomic distributions of resting cerebral perfusion defects in FTD and AD. They will assess the hypothesis that each FTD subgroup is associated with a core anatomic distribution of perfusion defect, including: l) reduced activity in superior and mesial frontal cortex in inattentive patients, 2) limited dorsolateral prefrontal (DLPFC) activity in dysexecutive patients, 3) diminished activity in inferior frontal and anterior superior temporal cortex (IFC) in PNFA patients, and 4) reduced anterior temporal and ventral frontal activity in patients with a bizarre affect. Correlative studies will test the hypothesis that dissociable executive components monitored by the cognitive battery are related to relatively specific neural substrates. Specific aim 3 focuses on the sentence comprehension deficit in FTD. Based on their model of sentence processing, they hypothesize that multiple factors contribute to FTD patients? difficulty, including a grammatical comprehension deficit on an on-line measure of sentence processing, impaired comprehension of verbs presented as film loops and definitions, and difficulty with strategic processing and short-term memory components of sentence comprehension on a dual-task procedure. They will assess the distribution of these deficits in FTD subgroups. Specific aim 4 seeks converging evidence from multiple sources for the neural basis of sentence comprehension. Correlative studies with perfusion fMRI in FTD patients, BOLD fMRI activation studies in younger and older healthy adults, and BOLD activation studies in FTD patients will be used to test the hypothesis that left IFC contributes to specific grammatical and short-term memory processes, and left DLPFC helps support strategic processing during sentence comprehension.